Synthesis of bis-spirocyclic derivatives of 3-azabicyclo[3.1.0]hexane via cyclopropene cycloadditions to the stable azomethine ylide derived from Ruhemann's purple

A reliable method for the synthesis of bis-spirocyclic derivatives of 3-azabicyclo[3.1.0]hexanes through the 1,3-dipolar cycloaddition (1,3-DC) reactions of cyclopropenes to the stable azomethine ylide – protonated form of Ruhemann's purple (PRP) has been developed. Both 3-substituted and 3,3-disubstituted cyclopropenes reacted with PRP, affording the corresponding bis-spirocyclic 3-azabicyclo[3.1.0]hexane cycloadducts in moderate to good yields with high diastereofacial selectivity. Moreover, several unstable 1,2-disubstituted cyclopropenes were successfully trapped by the stable 1,3-dipole under mild conditions. The mechanism of the cycloaddition reactions of cyclopropenes with PRP has been thoroughly studied using density functional theory (DFT) methods at the M11/cc-pVDZ level of theory. The cycloaddition reactions have been found to be HOMOcyclopropene–LUMOylide controlled while the transition-state energies for the reaction of 3-methyl-3-phenylcyclopropene with PRP are fully consistent with the experimentally observed stereoselectivity.


Experimental details and characterization data
General procedure A for the preparation of cycloadducts 3a-g, and 4: Protonated Ruhemann's purple (1, 121 mg, 0.400 mmol) and cyclopropene 2a-g, 2j (0.400 mmol) were dissolved in THF (15 mL). The reaction mixture was heated at reflux for 2-6 h and then cooled to room temperature.
The mixture was filtered through a plug of celite to remove trace amounts of an insoluble dark brown solid. The plug of celite was carefully rinsed with THF (20 mL). The filtrate was evaporated to dryness under vacuum. The crude residue was purified by recrystallization from a suitable solvent to obtain cycloadducts 3a-g, 4.
A choice was made between two possible configurations (structures 4 and 4') by a comparison of interproton distances with corresponding cross-peak intensities.
The distance 2.9 Å between H-C8 and protons of a methyl group (r H-C8 -Me ) was used as a reference; this value is almost the same for both structures 4 and 4'.
According to the well-known relationship S AB / S AC = (r AC / r AB ) 6  Finally, the distance between the methyl group and NH proton in diastereomer 4' is more than 5.0 Å, while there is a quite intensive cross-peak (2.82) which corresponds to the distance less than 3.0 Å.

X-ray data for compounds 3b and 3e
General procedure of the sample preparation and crystal structure determination: Single crystals of compounds 3b and 3e were grown by slow evaporation of their solutions in an ethanolchloroform mixture at room temperature. For single crystal X-ray diffraction experiments crystals were fixed on a micro mount and placed on at SuperNova, single source at offset/far, HyPix3000 or Xcalibur Eos diffractometers and were measured at 100 K using monochromated MoKα (3b) and CuKα (3e) radiations, respectively. The structures were solved by the ShelXT1 structure solution program using Intrinsic Phasing and the Superflip2 structure solution program using Charge Flipping and refined by means of the SHELXL program3 incorporated in the OLEX2 program package. Empirical absorption correction was applied in CrysAlisPro program complex using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. The crystallographic data and some parameters of refinement are collected in Tables S1 and S2.
Crystallographic data for compounds 3b and 3e have been deposited at the Cambridge Crystallographic Data Centre (Deposition nos. CCDC 2055282 (3b) and CCDC 2055281 (3e)) and can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif.

Calculation details
Computational methodology: The full geometry optimization of reactants, products, and transition state structures (TSs) were carried out at the DFT/HF level of theory using M11 hybrid exchange-correlation functional [15] and the cc-pVDZ basis set [16]. The polarizable continuum model (PCM) was used to calculate solvent effects of water and tetrahydrofuran [17]. The optimizations were performed using the Berny analytical gradient optimization method [18]. All